Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors.

Autor:	Yamamoto K; Institute for Cancer Genetics, Columbia Unviersity, New York, United States.; Department of Pathology and Cell Biology, Columbia University, New York, United States.; College of Physicians and Surgeons, Columbia University, New York, United States.; Pathobiology and Molecular Medicine Graduate Program, Columbia University, New York, United States., Wang J; Department of Biomedical Informatics, Columbia University, New York, United States.; Department of Systems Biology, Columbia University, New York, United States.; College of Physicians & Surgeons, Columbia University, New York, United States., Sprinzen L; Institute for Cancer Genetics, Columbia Unviersity, New York, United States.; Department of Pathology and Cell Biology, Columbia University, New York, United States.; College of Physicians and Surgeons, Columbia University, New York, United States.; Pathobiology and Molecular Medicine Graduate Program, Columbia University, New York, United States., Xu J; Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, United States., Haddock CJ; Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, United States., Li C; Institute for Cancer Genetics, Columbia Unviersity, New York, United States.; Department of Pathology and Cell Biology, Columbia University, New York, United States.; College of Physicians and Surgeons, Columbia University, New York, United States., Lee BJ; Institute for Cancer Genetics, Columbia Unviersity, New York, United States.; Department of Pathology and Cell Biology, Columbia University, New York, United States.; College of Physicians and Surgeons, Columbia University, New York, United States., Loredan DG; Institute for Cancer Genetics, Columbia Unviersity, New York, United States.; Department of Pathology and Cell Biology, Columbia University, New York, United States.; College of Physicians and Surgeons, Columbia University, New York, United States., Jiang W; Institute for Cancer Genetics, Columbia Unviersity, New York, United States.; Department of Pathology and Cell Biology, Columbia University, New York, United States.; College of Physicians and Surgeons, Columbia University, New York, United States., Vindigni A; Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, United States., Wang D; Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California San Diego, La Jolla, United States., Rabadan R; Department of Biomedical Informatics, Columbia University, New York, United States.; Department of Systems Biology, Columbia University, New York, United States.; College of Physicians & Surgeons, Columbia University, New York, United States., Zha S; Institute for Cancer Genetics, Columbia Unviersity, New York, United States.; Department of Pathology and Cell Biology, Columbia University, New York, United States.; College of Physicians and Surgeons, Columbia University, New York, United States.; Division of Pediatric Oncology, Hematology and Stem Cell Transplantation, Columbia University, New York, United States.; Department of Pediatrics, Columbia University, New York, United States.; College of Physicians & Surgeons, Columbia University, New York, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2016 Jun 15; Vol. 5. Date of Electronic Publication: 2016 Jun 15.
DOI:	10.7554/eLife.14709
Abstrakt:	Missense mutations in ATM kinase, a master regulator of DNA damage responses, are found in many cancers, but their impact on ATM function and implications for cancer therapy are largely unknown. Here we report that 72% of cancer-associated ATM mutations are missense mutations that are enriched around the kinase domain. Expression of kinase-dead ATM (Atm(KD/-)) is more oncogenic than loss of ATM (Atm(-/-)) in mouse models, leading to earlier and more frequent lymphomas with Pten deletions. Kinase-dead ATM protein (Atm-KD), but not loss of ATM (Atm-null), prevents replication-dependent removal of Topo-isomerase I-DNA adducts at the step of strand cleavage, leading to severe genomic instability and hypersensitivity to Topo-isomerase I inhibitors. Correspondingly, Topo-isomerase I inhibitors effectively and preferentially eliminate Atm(KD/-), but not Atm-proficientor Atm(-/-) leukemia in animal models. These findings identify ATM kinase-domain missense mutations as a potent oncogenic event and a biomarker for Topo-isomerase I inhibitor based therapy.
Databáze:	MEDLINE
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